Joint diseases are diseases which show damage and degeneration of joint cartilage as the main morbid states. Though a disease having the most frequent number of patients among joint diseases is osteoarthritis (OA) (Elders M. J., J. Rheumatol., 27, Suppl., 60, 6–8, 2000), analgesic anti-inflammatory drugs and hyaluronic acid preparations are used in the current therapeutic method merely as a symptomatic therapy for the purpose of alleviating pains accompanied by the degeneration of cartilage and the destruction of subchondral cartilage, so that it cannot be said that they are exerting sufficient therapeutic effects (Dieppe P., Scand. J. Rheumatol., 29, 279–281, 2000).
Joint cartilage is a tissue mainly composed of type II collagen and aggrecan which is a cartilage-specific proteoglycan, and degradation and degeneration of both of them are observed in the joint diseases. Because of this, it has been considered for a long time that control of the degradation and degeneration of these extracellular matrix components would lead to the treatment of joint diseases, so that attempts have been positively made to identify degradation-concerned proteases (collagenase and aggrecanase) and to screen their inhibitors and develop them as medicaments.
As proteases having collagenase activities, matrix metalloproteases (MMP1, MMP8, MMP13, MMP14 and the like) have been identified, and their selective inhibitors have been discovered. However, in spite of the attempts to develop a large number of MMP inhibitors having collagenase inhibition activities as therapeutic drugs for joint diseases including OA and rheumatic arthritis (RA), MMP inhibitors to be used in these diseases as the indication have not been put on the market (Greenwald R. A., Ann. New York Acad. Sci., 878, 413–419, 1999). Under such circumstances, attention has been directed toward aggrecanase which selectively degrades aggrecan which is another main constituting component of joint cartilage.
A joint disease-related role of an enzyme aggrecanase which cleaves aggrecan at the site between Glu373-Ala374 has been revealed by the reports of Sandy et al. and Lohmander et al. stating that all of the main digested aggrecan fragments found in the synovial fluid of human arthritis patients were generated by cleaving at the aggrecanase digestion site (Sandy J. D. et al., J. Clin. Invest., 89, 1512–1516, 1992; Lohmander L. S. et al., Arthritis Rheum., 36, 1214–1222, 1993). On the other hand, it has been known that, in an in vitro explant culture system of joint cartilage, degradation of aggrecan firstly occurs by IL-1 induction and then degradation of type II collagen is accelerated (Dingle L. T. et al., Ann. Rheum. Dis., 34, 303–311, 1975; Cawston T. E. et al., Biochem. Biophys. Res. Comm., 215, 377–385, 1995; Kozaci L. D. et al., Arthritis Rheum., 40, 164–174, 1997). It has been reported that the aggrecan degradation takes the precedence of the type II collagen degradation in a mouse arthritis model too (van Meurs J. B. et al., Arthritis Rheum., 42, 1128–1139, 1999). These reports suggest a possibility that the type II collagen degradation can be controlled by inhibiting the preceding aggrecan degradation.
However, although biochemical features show that it is a metalloprotease, that it is located on the outside of cells, that sugar chains contribute to a substrate recognition, and that an activity is induced by IL-1, TNF, or retinoic acid, aggrecanase as a cause of joint diseases has been unidentified for a long time. Recently, ADAMTS4 (aggrecanase-11; Tortorella M. D. et al., Science, 284, 1664–1666, 1999) and ADAMTS11 (aggrecanase-2; Abbaszade I. et al., J. Biol. Chem., 274, 23443–23450, 1999) were reported as the protease having the aggrecanase activity. However, the gene expressions of these proteases are not increased in human OA cartilage and not induced by IL-1, TNF, or retinoic acid (it is known that these compounds induce the aggrecanase activity in an explant culture system of human knee articular cartilage), and thus the presence of another protease relating to joint diseases was suggested (Flannery C. R. et al., Biochem. Biophys. Res. Commun., 260, 318–322, 1999).
In addition, recently, chromosomal loci in which genetic factors relating to OA are located (an OA-susceptibility locus) in accordance with a genetic research for patients suffering from OA or families having a strong family history of OA have been identified. For example, 11q (Chapman K. et al., Am. J. Hum. Genet., 65, 167–174, 1999), 4q12–4q21.2, 6q21.1–6q22.1, 16p13.1–16q12.1, and 16q21–16q23 (Loughlin J. et al., Am. J. Hum. Genet., 65, 1795–1798, 1999) are reported as the OA-susceptibility loci.